JP5382700B2 - Rod-shaped porous silica particles - Google Patents

Description

  The present invention relates to rod-shaped porous silica particles excellent in monodispersibility, and further relates to a production method thereof and application to an in vivo implant material, a silicon sustained-release drug, and the like.

  Since the synthesis method of porous MCM-41 was published in Nature in 1992, interest in mesoporous materials has increased, and many studies using ionic surfactants such as quaternary ammonium salts have been reported. Later, it was reported that non-toxic, biodegradable, easy removal, and mesoporous materials could be synthesized using inexpensive oligomer or polymer nonionic surfactants as templates. (Non-Patent Document 1).

  On the other hand, from the beginning of the creation of mesoporous materials, not only the regular structure of mesopores but also the development of porous materials having a high-order ordered structure controlled from micron to millimeter-sized macro form has attracted attention (Non-Patent Document 2). ). In particular, recently, the adsorption phenomenon of mesoporous silica remarkably depends on the macro form, and the form control is an important research subject.

  The present inventors previously described a dual pore structure in which long mesochannel pores are connected by micropores in a gas adsorption phenomenon of volatile organic compounds (VOC) of fibrous porous silica particles in which rod-like particles are linked. It was clarified that the high VOC adsorption ability and the easy desorption ability are exhibited due to the above (Non-patent Document 3). In addition, in the adsorption phenomenon in the solution, the rod-shaped particles, which are the basic structural units of the fibrous particles, have a larger contact area with the adsorbate, so the adsorption speed is faster than the fibrous particles, for example, In the adsorption of an enzyme or the like having a large molecular weight, a rod-like particle having a large mesopore and a smaller particle diameter is recognized to have a remarkable adsorption effect (Non-patent Document 4).

  On the other hand, to enable the development of mesoporous silica applications, it is essential to establish an efficient mass production process, and it is extremely important to use an inexpensive silica source such as alkali silicate as a starting material. It is possible (Non-Patent Document 5).

However, although the synthesis method using an alkali silicate which is an inexpensive silica source and a nonionic surfactant is well known, both compounds can be used simultaneously, without adding other substances, and with the pore size There are very few reports of controlling the macro form (Non-patent Document 6 and Non-patent Document 7).
The reason is that it is very difficult to find an efficient method for controlling the macro morphology as well as controlling the pore diameter. Actually, for example, Patent Document 1 reports a method for synthesizing mesoporous silica using an acidic solution of sodium silicate and a nonionic surfactant as a raw material. Etc. are not described at all, and it is presumed from the X-ray diffraction pattern that the regularity of the mesostructure of the obtained product is extremely low.

  In addition, there have been several reports on mesoporous silica whose shape has been controlled in the form of a rod so far. Limited to examples using silica. In addition, when alkoxysilane is used, the aspect ratio of the rod-like particles is generally 1 or more (Non-patent Document 8), and in order to further improve the monodispersity and make the aspect ratio less than 1, it is organic. Addition of other substances such as compounds is considered essential.

  For example, small particulate mesoporous silica with large mesopores that exhibit an effective function for enzyme adsorption is synthesized through a complex reaction process using alkoxysilane and further adding fluorides and alkanes. (Non-patent document 9).

In such a background, the present inventors have found that the control of macro form and the regularity of high mesostructure are important points for the development of mesoporous materials by an efficient synthesis method using low-cost raw materials. We have been studying based on our thoughts, and have made new technical proposals based on the knowledge gained in the process.
For example, rod-like and fibrous porous silica particles (Patent Literature 2) and spherical silica porous materials (Patent Literatures 3 and 4) using a triblock copolymer as an alkali silicate and a nonionic surfactant. A synthesis method is proposed.

  In the former method for synthesizing rod-like and fibrous porous silica particles, sodium silicate and a triblock copolymer (trade name Pluronic P123) are reacted in an acidic hydrochloric acid solution. Silica mesoporous material is selectively synthesized.

  In addition, in the method for producing thin plate-like porous silica particles of Patent Document 5, the length of the rod is about 0.2 μm and the aspect ratio is 0.2 or less by exchanging Si of the silica skeleton with another metal. However, it is not possible to obtain rod-like silica particles having an aspect ratio of less than 0.1 to 1 comprising a pure silica component.

  Furthermore, recently, a thin plate-like porous particle was published as a new substance in an acidic solution, and a plate-like silica was obtained by substituting Si with another metal, specifically Zr, as in the production method of the inventors. Has been reported (Non-patent Document 10).

  On the other hand, regarding the use of mesoporous silica as a material for embedding in living tissue or a sustained-release silicon drug, drug delivery carriers (Non-patent Documents 11 and 12), gene introduction agents (Non-patent Document 13), immunostimulators (non-patent documents) The use of Patent Document 14) is considered promising. In addition, since Si is an essential element for bone tissue formation and connective tissue formation, it can be used as a drug that releases silicon in vivo.

However, when silica materials including mesoporous silica are generally used as living implants or drugs, cytotoxicity that is taken into cells and destroys cells may become a problem (Non-patent Document 15). 16).
This cytotoxicity mainly depends on the particle size and particle concentration. That is, since the cytotoxicity increases as the particles become smaller, it is necessary to lower the concentration of the particles when the particle diameter is reduced. Therefore, in order for mesoporous silica to exert its effect as a biomaterial or a drug, it is necessary to specify a particle concentration range that does not exhibit cytotoxicity in accordance with the particle diameter as well as optimization of pore characteristics. When applying mesoporous silica as a bio-implant material or a sustained-release drug for silicon, considering the cell size, affinity with the living body, and safety, it is important that the particle size is 20 μm or less and that it does not exhibit cytotoxicity. Conceivable.

By the way, in the rod-like particles described in the above-mentioned Patent Document 2 of the present inventors, the form of each particle is clear and can be applied to uses such as an adsorbent and a catalyst carrier. It is easy to obtain as a large aggregate having a particle size distribution peak value of about 20 μm, and when used as a bio-implant material or a drug, secondary production such as development of a new production method or disintegration that enables further dispersion Processing is required. Moreover, the length of each particle is in the range of 0.5 to 5 μm, and it is an elongated particle characterized by an aspect ratio of 1.1 to 15, and it can be said that it is suitable as a bio-implant material from the viewpoint of the particle form. Absent.
Moreover, the thin plate-like porous silica particles of Patent Document 5 are plate-like particles having a rod length (particle thickness) of about 0.2 μm and an aspect ratio of 0.2 or less. It is indispensable to exchange Si of the silica skeleton with other metals such as Zr, so that a big problem arises from the viewpoint of safety in order to obtain a biomaterial.

  As described above, it is possible to synthesize a small porous silica material having no cytotoxicity using an inexpensive alkali silicate as a silica source. Although it is an important issue to be overcome in order to develop the field of use, there are very few reported examples compared to those using organic silicon such as expensive alkoxysilane as a raw material, and a macro combined with a nonionic surfactant. Reports on morphological control are very limited.

In addition, a simple reaction system that does not use an organic compound as an additive has a length of 0.5 μm or less, an aspect ratio of less than 1, and a high mesostructured regularity. So far, no rod-shaped porous silica particles composed of a pure silica component whose maximum value is 10 μm or less and a production method thereof have not been reported.
Furthermore, due to the high-temperature dehydration behavior of the nonionic surfactant used, the rod-shaped porous silica particles have micropores simultaneously with mesopores of 7 nm or more, and the aging temperature is less than 150 ° C. In this case, the ratio of the micropore volume to the total pore volume (pore volume resulting from both mesopores and micropores) after heat treatment at 600 ° C. is 10% or more. On the other hand, when the aging temperature is 150 ° C. or higher, only rod-like particles having only mesopores having no micropores are obtained.

JP 2001-261326 A Japanese Patent No. 40998811 JP 2004-182492 A JP 2004-143026 A JP 2006-151799 A

Bagshaw, S.A .; Prouzet, E .; Pinnavaia, T.J.Science 1995, 269, 1242. 1) Ciesla, U .; Schuth, F. Microporous Mesoporous Mater. 1999, 27, 131. 2) Stein, A. Adv. Mater. 2003, 15, 763. 3) Kosuge, K. Kubo, S. Kikukawa, N. Takemori, M. Langmuir, 2007, 23, 3095. Fan, J. Lei, J. Wang, L. Yu, C. Tu, B. Zhao, D. Chem. Comm., 2003, 2140. 1) Sierra, L .; Guth, JL. Microporous Mesoporous Mater. 1999, 28, 243. 2) Kim, SS; Pauly, TR; Pinnavaia T.J. Chem. Commun. 2000, 835. 3) Kim, SS; Pauly , TR; Pinnavaia TJ Chem. Commun. 2000, 1661. Boissiere, C .; Larbot, A .; van der Lee, A .; Kooyman, P.J .; Prouzet, E. Chem. Mater. 2000, 12, 2902. Sun, Q .; Kooyman, P.J .; Grossmann, J.G .; Bomans, P.H.H .; Frederik, P.M .; Magusin, P.C.M.M .; Beelen, T.P.M .; van Santen, R.A .; Sommerdijk, N.A.J.M.Adv. 97. Sayari, A; Han, B-H .; Yang, Y. J. Am. Chem. Soc., 2004, 126, 14348. Sun, J. M .; Zhang, H .; Tian, R. J .; Ma, D .; Bao, X. H .; Su, D. S .; Zou, H.F. Chem. Commun. 2006, 1322. Chen, SY .; Tang, CY .; Chuang, WT .; Lee, JJ .; Tsai, YL .; Chan, JCC; Lin, CY .; Liu, YC .; Cheng, S., Chem. Mater. 2008, 20, 3906. Vallhov, H .; Gabrielsson, S .; Stromme, M .; Scheynius, A .; Garcia-Bennett, A.E; Nano Letters 2007, 7, 3576. Blumen, S.R .; Cheng, K .; Ramos-Nino, M.E .; Taatjes, D.J .; Weiss, D.J .; Landry, C.C .; Mossman, R.T .; Am J Respir Cell Mol Biol 2007, 36, 333. Radu, D. R .; Lai, C.-Y .; Jeftinija, K .; Rowe, E. W .; Jeftinija, S .; Lin, V. S.-Y .; J. Am. Chem. Soc. 2004, 126, 13216. Mercuri, L.P .; Carvalho, L. V .; Lima, F.A .; Quayle C et al., Small 2006, 2, 254. Di Pasqua, A.J .; Sharma, K.K .; Shi, Y-L .; Toms, B.B .; Ouellette, W .; Dabrowiak, J.C .; Asefa, T .; J. Inorganic Biochem. 2008, 102, 14416. Hudson, S.P .; Padera, R.F .; Langer, R .; Kohane, D.S .; Biomaterials 2008, 29, 4045.

As described above, in the method for producing rod-shaped porous silica particles of Patent Document 2 by the present inventors, the monodispersibility is improved and the fine dispersion is maintained while maintaining the rod-shaped form in order to produce the rod-shaped porous silica particles at a relatively low temperature. There was a limit to the expansion of the hole diameter. And in the manufacturing method of the thin plate-like porous silica particle of the above-mentioned patent document 5, the length of the rod-like particle is about 0.2 μm and the aspect ratio is 0.2 or less, but Si in the silicate skeleton is changed to Zr. There is a problem that pure rod-like porous silica particles cannot be produced because substitution with a metal element such as is required.
The present invention has been developed by the present inventor so far to solve these conventional problems and use an inexpensive alkali silicate as a silica source and a non-toxic or low-toxic nonionic surfactant as a template. Based on our technical knowledge, we provide industrial production technology for rod-shaped porous silica particles whose aspect ratio is controlled to less than 0.1 to 1, and a new rod-shaped porous material with excellent monodispersity consisting of pure silica components. It is an object of the present invention to provide a bio-implanting material and a sustained-release drug for silicon that are safe for a living body using the silica particles.

  The present inventor has intensively studied to solve the above problems, and is an acidic aqueous solution reaction system of an alkali silicate solution and a triblock copolymer. By controlling the temperature at the same time, or preliminarily adding a metal salt and aging under hydrothermal conditions, the degree of dispersion can be further enhanced, and the silica purity is controlled to a length of 0.5 μm or less with an aspect ratio of less than 1. It has been found that porous silica particles having a rod-like form with excellent monodispersibility composed of components can be obtained, and, further, mesoporous silica can be used as a bio-implanting material, in spite of small particles having a particle size distribution peak of 10 μm or less. It has been found that there is almost no cytotoxicity, which is a problem when used as a drug, and it can be used as an in-vivo implant material that is safe for the living body or a silicon sustained-release drug. The present invention has been completed based on such knowledge.

That is, this application provides the following inventions.
<1> According to transmission and scanning microscope observations, the particle length in the direction through which the one-dimensional channel-shaped pores with a mesopore diameter of 3 nm or more arranged in a honeycomb shape penetrate is 0.5 μm or less. When the ratio with the length of the vertical particle cross section is the aspect ratio (= the length of the particle in the direction through which the pores penetrate / the length of the particle cross section perpendicular to the particle extension direction) , the aspect ratio is 0.1. Particles having a rod-like morphology of less than ˜1, and forming a loose aggregate in which the maximum value of the particle size distribution peak (volume basis) in an aqueous dispersion is 10 μm or less. rod porous silica particles to feature that Si element has not been substituted by other metals.
<2> The rod-shaped silica porous particle according to <1>, which has a plurality of X-ray diffraction peaks indicating a regular arrangement structure of pores at a diffraction angle of 0.5 to 5 degrees (CuKα).
<3> A suspension or dispersion containing 2 to 300 μg / mL of the rod-like silica porous particles according to <1> or <2>.
<4> A mixture of an acidic aqueous solution and a nonionic surfactant is mixed with an aqueous alkali silicate solution while stirring under a temperature condition of 45 ° C. to less than 60 ° C., and within a reaction time in which no cloudiness is observed in the reaction solution. After the stirring is stopped, the solid product obtained by aging at a temperature in the range of 50 ° C. to 200 ° C. is separated, washed and dried, and then the nonionic surfactant is removed <1 > Or <2> The method for producing rod-like silica porous particles according to <2>.
<5> A mixture of an acidic aqueous solution and a nonionic surfactant is mixed with an aqueous alkali silicate solution with stirring under a temperature condition of 45 ° C. to less than 60 ° C., and within a reaction time in which no cloudiness is observed in the reaction solution. The solid product obtained after aging for 10 to 120 minutes, followed by separation and washing is kept in a wet state or after drying in an aqueous solution at a temperature in the range of 50 ° C to 200 ° C. The method for producing rod-like silica porous particles according to <1> or <2>, wherein after solidification, the solid product is separated, washed and dried, and then the nonionic surfactant is removed.
<6> A mixture of an acidic aqueous solution and a nonionic surfactant is mixed with an aqueous alkali silicate solution while stirring under a temperature condition of 45 ° C. to less than 60 ° C., and within the reaction time in which no cloudiness is observed in the reaction solution. The solid product obtained by aging for 10 to 120 minutes and then separating and washing is left in a wet state or dried and then dissolved in an aqueous solution in which the metal salt is dissolved. The rod-like silica porous particles according to <1> or <2>, wherein the solid product is separated, washed and dried after aging at a temperature in the range of <1> or <2> Manufacturing method.
<7> according to any one of which comprises using an amount of SiO ₂ 1 mole per 0.01 to 0.10 moles of non-ionic surfactant in an alkaline silicate <4> to <6> Production method.
<8> The method according to any one of <4> to <7>, wherein the acid is used in an amount of 5 to 20 moles per mole of SiO ₂ in the alkali silicate.
<9> The method according to any one of <4> to <8>, wherein water is used in an amount of 100 to 400 mol per mol of SiO ₂ in the alkali silicate.
<10> The production method according to any one of < 6 > to <9>, wherein the metal salt is used in an amount of 0.01 to 1 mol per 1 mol of SiO ₂ in the alkali silicate.
<11> A living material containing the rod-shaped porous silica particles according to <1> or <2>.
<12> A sustained-release silicon drug containing the rod-shaped porous silica particles according to <1> or <2>.
<13> An in-vivo embedding material containing the suspension or solvent liquid according to <3>.
<14> A silicon sustained-release drug containing the suspension or particle solvent mixed system according to <3>.

Since the rod-shaped porous silica particles according to the present invention have characteristics such as a high specific surface area, uniform pore diameter, and monodispersity, a sustained-release silicon drug for sustained release of bioimplantable materials and silicon Since there is almost no cytotoxicity that becomes a problem when used as, it can be used in these applications.
In addition, according to the method of the present invention, a nonionic surfactant is used as a pore structure control agent, and other organic compounds are added in a very simple reaction system in which an alkali silicate aqueous solution and an acidic aqueous solution are mixed. Without changing the mixing ratio of the reactants, stirring and aging reaction temperature, and further stirring and aging reaction time, the rod-shaped organic inorganic mesostructure containing the surfactant that becomes the precursor of the rod-shaped porous body To obtain rod-shaped porous silica particles having a length of 0.5 μm or less, an aspect ratio of less than 0.1 to 1, and excellent silica monocomponent monodispersibility by finally removing organic matter. Can do.
Moreover, according to the production method of the present invention, it is possible to produce a rod-shaped organic inorganic mesostructure containing a surfactant that is a precursor of rod-shaped porous silica particles in an extremely short time of 10 minutes to several hours. The rod-shaped organic-inorganic mesostructure containing the surfactant produced therein can be aged in an acidic solution as it is, or can be aged after being separated and washed from the acidic solution.
In addition, according to the manufacturing method of the present invention, not only a rod-like macro form but also a one-dimensional mesochannel having an aperture diameter of 7 nm or more having a honeycomb-like regular structure, as well as pure silica in which a mesochannel and a micropore coexist. The component rod-like porous silica particles can be obtained.
Furthermore, since the production method of the present invention uses an inexpensive raw material and most of the reaction time is a aging step by standing or stirring conditions, it can be easily applied to an industrial scale.

The conceptual diagram of one rod-shaped porous silica particle of this invention. The TEM image of the rod-shaped porous silica particle of this invention. 3 is an SEM image of rod-shaped porous silica particles of Comparative Example 1. FIG. (A) SEM image of rod-shaped porous silica particles of Comparative Example 2-1. (B) SEM image of rod-shaped porous silica particles of Comparative Example 2-2. The FE-SEM image of the rod-shaped porous silica particle of Example 1-1. The FE-SEM image of the rod-shaped porous silica particle of Example 2-1. The FE-SEM image of the rod-shaped porous silica particle of Example 3-4. The particle size distribution curve of the rod-shaped porous silica particle of Example 2-1 and Comparative Example 3. The particle size distribution curve of the rod-shaped porous silica particle of Example 2-1, Example 3-1, Example 3-4, and Example 3-5. (A), (b): TEM image of rod-shaped porous silica particles of Example 3-5. The X-ray-diffraction pattern of the rod-shaped porous silica particle of Example 2-1, Example 3-1, and Example 3-5. The nitrogen adsorption isotherm of the rod-shaped porous silica particle of Example 2-1, Example 3-1, and Example 3-5. The BJH pore distribution curve of the rod-shaped porous silica particle of Example 2-1, Example 3-1, and Example 3-5. The t-plot obtained from the nitrogen adsorption isotherm of the rod-shaped porous silica particle of Example 2-1, Example 3-1, and Example 3-5. The graph showing the change of the number of cells after culture | cultivating NIH3T3 cell for 72 hours in the cell culture solution containing the rod-shaped porous silica particle of Example 3-4. The graph showing the change of the number of cells after culture | cultivating NIH3T3 cell for 72 hours in the cell culture solution containing the rod-shaped porous silica particle of Example 3-5. The graph showing the change of the silicon concentration of a cell culture solution after culturing NIH3T3 cell for 72 hours in the cell culture solution containing the rod-shaped porous silica particle of Example 3-4 and Example 3-5.

  The rod-like silica porous particle of the present invention has a particle length of 0.5 μm in a direction through which a one-dimensional channel-like pore having a mesopore diameter of 3 nm or more regularly arranged in a honeycomb shape penetrates through transmission and scanning microscope observations. In the following, when the aspect ratio is the ratio to the length of the particle cross section perpendicular to the particle extension direction, the particles have a rod-like form with an aspect ratio of less than 0.1 to 1, and the particle size in an aqueous dispersion system It is characterized in that the Si element in the silica skeleton forming a loose aggregate whose maximum distribution peak (volume basis) is 10 μm or less is not substituted with another metal.

The rod-like silica porous particles of the present invention are schematically shown in FIG. In FIG. 1, L is the length of a particle (the length of a rod-shaped particle) in a direction through which a one-dimensional channel-shaped pore having a mesopore diameter of 3 nm or more arranged regularly in a honeycomb shape passes, and W is in the particle stretching direction. It is the length of the vertical particle cross section (the width of the rod-like particle), and the aspect ratio is expressed by L / W.
Therefore, the rod-like silica porous particles of the present invention have a mesopore diameter of 3 nm or more, preferably 4 to 20 nm, L of 0.5 μm or less, preferably 0.15 to 0.45 μm, as shown in FIG. It means particles having a ratio (L / W) of less than 0.1 to 1, preferably 0.15 to 0.5.
If L exceeds 0.5 μm, it is expected that the one-dimensional mesochannel will be long and mass transfer in the pores will be suppressed, and if the aspect ratio is less than 0.1, the particles will be extremely thin and monodispersed. If it is 1 or more, it is difficult to adjust the synthesis conditions, and long and short mixed heterogeneous particle groups are likely to be formed.

Further, the rod-like silica porous particles of the present invention are characterized in that they form a loose aggregate in which the maximum value of the particle size distribution peak (volume basis) in the aqueous dispersion is within a range of 10 μm or less. Further, the Si element in the silica skeleton is not substituted with another metal.
Here, the maximum value of the particle size distribution peak (volume basis) in the water dispersion means a value measured by a particle measurement method based on the laser diffraction scattering principle, and in the present invention, this value is in a range of 10 μm or less. Therefore, rod-shaped porous silica particles having excellent monodispersibility can be obtained.

  Here, as shown in the TEM image of FIG. 2, the particles having excellent monodispersity are composed of individual particles and loose aggregates as shown in the schematic diagram of FIG. The “loose aggregate” means that one-dimensional mesopores in a channel form are regularly arranged in a honeycomb shape in each particle, and for example, molecules or ions from the outside world enter the pores of each particle. It means a group of particles that can be contacted with equal probability.

  Furthermore, in the rod-like silica porous particles of the present invention, it is important that the Si element in the silica skeleton is not substituted with another metal. This is because if the skeleton is replaced with another metal, problems such as unexpected cytotoxicity may occur depending on the type of metal.

Hereinafter, the rod-like silica porous particles of the present invention will be described more specifically.
The rod-shaped porous silica particles of the present invention are obtained from the field emission scanning electron microscope (FE-SEM) shown in FIG. 5 (Example 1-1, FIG. 6 (Example 2-1), and FIG. 7 (Example 3-4). ) As shown in the photograph, it has a micron-sized rod-like shape and an aspect ratio is uniform.
FIG. 8 compares the particle size distribution of the rod-shaped porous silica particles of Example 2-1 of the present invention and Comparative Example (Patent Document 2). In the present invention, the aging process is performed at a higher temperature, which is a major difference from the prior application (Patent Document 2), and even when the stirring temperature is the same, the particle size distribution varies significantly depending on the aging temperature, and the degree of aggregation is remarkably reduced. I understand that.

  FIG. 9 shows the characteristics of the particle size distribution of the rod-like porous silica particles of Examples 2-1, 3-1, 3-4 and 3-5 of the present invention. From FIG. 8, it can be seen that the maximum peak of the particle size distribution is present in the rod-shaped porous silica particles of the present application at 10 μm or less with respect to the peak value (volume basis) of 20 μm in the particle size distribution of Patent Document 2. It is clear that aging at high temperatures significantly improves the degree of aggregation and that monodispersion is further promoted by the addition of metal salts.

  FIG. 10 is a high-resolution electron microscope (TEM) photograph showing the extension direction and the cross-sectional structure of the rod-shaped porous silica particles of Example 3-5 of the present invention. In the rod-shaped porous silica particles of the present invention, it is shown that the one-dimensional mesochannels (FIG. 10a) having a uniform diameter extending through the rod-shaped particles are regularly arranged in a honeycomb shape (FIG. 10b). ).

  Furthermore, the rod-shaped porous silica particles of Example 2-1, Example 3-1, and Example 3-5 of the present invention have a diffraction angle 2θ = 0.5 as shown in the XRD diffraction pattern of FIG. This corresponds to the fact that mesochannels having a plurality of peaks indicating a regular arrangement of mesopores at ˜5.0 degrees and being observed in the TEM image of FIG. 10 are stacked in a honeycomb shape.

  FIG. 12 is an adsorption isotherm of the rod-shaped porous silica particles of Example 2-1, Example 3-1, and Example 3-5 of the present invention, and is typical based on the high regularity of the mesostructure. A typical IV-type adsorption isotherm and HI-type hysteresis, which is a feature of cylindrical pores, are observed, and the pore size distribution is sharp as shown in FIG. 13, confirming the uniformity of mesopores. Moreover, FIG. 14 is t-plot, and since the intercept between the straight line M and the vertical axis is a positive value, the presence of micropores is clear, and the micropore volume was calculated from the value of the intercept. In the case of rod-shaped particles aged at 150 ° C., the straight line M ′ passes through a point very close to the origin, indicating that there are almost no micropores. The total pore volume of the present application is the sum of mesopores and micropores, and is determined from the amount of adsorption corresponding to the intercept between the straight line N (N ′) of the t-plot and the vertical axis.

Below, the manufacturing method of the rod-shaped porous silica particle of this invention is demonstrated.
In the method for producing rod-shaped porous silica particles of the present invention, first, an alkali silicate aqueous solution is mixed at 45 ° C. to less than 60 ° C., preferably 45 ° C. to 55 ° C., in a mixed solution of an acidic aqueous solution and a nonionic surfactant. Mixing is performed under stirring under temperature conditions, and stirring is stopped while no turbidity due to precipitation of particles from the reaction solution is observed after a certain period of time. There are two methods for the aging step following this stirring step.

  In the first method, after the stirring is stopped, the reaction vessel is heated as it is or transferred to a constant temperature reactor maintained at a constant temperature, and is kept at a constant temperature of 50 to 200 ° C. Aging is performed at a temperature of 60 ° C. to 150 ° C. for a predetermined time.

  In the second method, after the stirring is stopped, the rod-shaped organic-inorganic nanocomposite is once separated from the acid solution by aging for 10 minutes to 120 minutes, preferably 20 minutes to 90 minutes, with stirring as it is or slowly. After washing, it is characterized by aging at a constant temperature of 50 ° C. to 200 ° C., preferably 60 ° C. to 150 ° C. for a predetermined time while standing or stirring in a constant temperature reactor maintained at a constant temperature.

  However, both methods are common in that after the ripening step is completed, the produced solid is separated and washed, and after drying, the nonionic surfactant is removed.

  In the above method, the stirring temperature is set to 45 ° C. to less than 60 ° C. When the temperature is 45 ° C. or less, rod-like particles having an aspect ratio of 1 or more are easily formed in the final product. This is because dehydration of the hydrophilic group portion in the surfactant is likely to occur, so that the formation of rod-like particles having a homogeneous shape is hindered, and the high regularity of the mesostructure is impaired.

The aging temperature is in the range of 50 ° C. to 200 ° C. The effect is not obtained even when aging is performed for a long time at 50 ° C. or less, and the regularity of the meso structure is compared with 150 ° C. at 200 ° C. or more. Moreover, it is because a remarkable difference cannot be found in monodispersity. Further, the aging time in the range of 60 ° C. to 150 ° C. may be shorter as the aging temperature is higher, and when it is 150 ° C., 1 hour is sufficient, and when it is lower, aging may be performed for several tens of hours. .
In the ripening step after the stirring step, the ripening time is set to 10 minutes to 120 minutes. When the ripening time is 10 minutes or less, the amount of rod-shaped particles generated is too low and the reaction efficiency is lowered. This is because no significant difference is found in the amount produced.

  Furthermore, in this production method in two stages of stirring and aging process, the aging temperature is an important condition for forming a rod-like organic inorganic mesostructure having excellent monodispersibility and an aspect ratio of less than 0.1 to 1. The coexistence effect of the salt in addition to the control of the above will be described.

As a reaction condition in which salts do not coexist at all, when tetraethylorthosilicate (TEOS) is used as a silica source instead of alkali silicate, the length is controlled to 0.5 μm or less in a short reaction according to the present invention, Moreover, it is difficult to find conditions for producing rod-shaped particles having a homogeneous shape.
When the stirring reaction is carried out at 30 ° C to less than 60 ° C, it is difficult to produce rod-shaped porous silica having the features of this method regardless of the aging temperature. For example, stirring is carried out at 45 ° C and aging is carried out at 100 ° C. In the case of no addition of NaCl, long rod-shaped particles having an aspect ratio of 1 or more are formed (FIG. 4a), but when NaCl is added, the morphology changes significantly, and in addition to the long rod-shaped particles, small particles are aggregated. Aggregation is observed (Figure 4b).

  On the other hand, when sodium silicate is used as the silica source, as shown in the examples of the present application, when stirring is performed at 45 ° C. or higher, rod-shaped particles having an aspect ratio of 1 or more are not formed even when the aging temperature is increased. Organic silicon-based silica sources such as TEOS have a slower hydrolysis rate than water-soluble silica sources such as alkali silicates, and it is difficult to control the crystallization rate. In addition, other substances such as alcohols are used to homogenize the reaction solution. Or a long stirring reaction is required, and there is a problem that particles are likely to aggregate.

  This indicates that in order to induce the formation of short rod-shaped particles, it is important to perform stirring at a certain temperature or higher in the presence of salts. In the case where salts do not coexist, rod-shaped particles having a large mesopore diameter are produced. Therefore, when aging is performed at a high temperature, elongated particles having an aspect ratio of 1 or more are easily formed. In particular, it is suggested that the presence of cations in the salt exerts an important effect on morphology control, and the alkali silicate solution contains alkali metal ions in the raw material, which is optimal for producing short rod-like particles. It can be said that it is a silica raw material. The coexisting cation lowers the critical micelle concentration of the surfactant, promotes the silica condensation by increasing the ionic strength and the effect of homogenizing the aqueous solution, and is useful for the formation of short rod-like organic inorganic mesostructures. It is considered to play a role.

  These experimental facts indicate that when forming an organic-inorganic mesostructure under reaction (mixture of raw material) conditions that easily form a rod-like form, the condensation rate of the silica component surrounding the rod-like micelle is increased, and individual rod-like organic substances are formed. Inhibiting the aggregation between the structures by significantly promoting the formation of the silica skeleton structure in the inorganic mesostructure is an important point for producing rod-shaped particles with good monodispersity. ing.

The production mechanism of rod-like porous particles in which mesopores are regularly arranged in a honeycomb shape while exhibiting a rod-like shape of 0.5 μm or less by the production method of the present invention is estimated as follows.
Alkali silicates have positively charged silica dissolved species in a strongly acidic aqueous solution [I ⁺ ], while nonionic surfactants [N ⁰ ] dissolved in strong acids also have hydrophilic groups on the surface of the surfactant. It is positively charged by being covered with proton [H ⁺ ], and an anion [X ⁻ ] is interposed between both surfaces of the positively charged silica and the surfactant, so that an electrically stable organic-inorganic meso It is presumed to form the structure [N ⁰ H ⁺ ] [X ⁻ I ⁺ ].

Furthermore, the solution contains alkali ions (M ⁺ ) generated by the reaction between the alkali silicate and the acid, and the charges between the silicas whose surfaces are charged are offset by these ions. It proceeds to produce an organic-inorganic mesostructure containing a nonionic surfactant in the silica skeleton.
That is, by selecting a nonionic surfactant [N ⁰ ] so that the organic-inorganic mesostructure can easily form a rod-like structure, particles having a micron-order rod-like morphology can be obtained. In order to shorten the rod length while maintaining the structure of the organic-inorganic mesostructure [N ⁰ H ⁺ ] [X ⁻ I ⁺ ] at this time, it is necessary to increase the temperature to be formed as high as possible. It is estimated to be effective. Further, at the stage where this structure is aggregated and formed as one rod-like particle, it is aged at a higher temperature, and the condensation of silica in one particle proceeds rapidly, resulting in the desired monodispersity. It is considered that rod-like particles excellent in the above can be easily obtained.

  That is, the rod-shaped porous silica particle precursor is formed by improving the regularity of the mesostructure while suppressing the aggregation between the rod-shaped organic inorganic mesostructures and the growth in the mesochannel direction, and the organic component The final product obtained by removing by baking or solvent extraction or the like exhibits a rod shape with an aspect ratio of less than 0.1 to 1 as shown in FIG. Together with regularly arranged mesopores, it has an ordered structure at two different scales.

  In addition, the higher the aging temperature, the larger the hydrophobic portion of the nonionic surfactant, and the dehydration condensation of the silica phase forming the rod-shaped organic inorganic mesostructure that is the precursor of the rod-shaped porous silica particles. When the silica phase progresses more rapidly and the silica phase contracts, the internal micelle phase induces a wider space, and rod-like silica having large mesopores is obtained. In addition, the hydrophilic group of the surfactant constituting the rod-shaped organic-inorganic mesostructure has penetrated into the silica skeleton, and micropores are formed along with the removal, and the mesopores of the resulting porous body are connected by the micropores. Will be. At this time, when the aging temperature is increased, the hydrophilic group tends to be hydrophobic, and when aging is performed at 150 ° C., rod-shaped porous silica particles having almost no micropores are obtained.

As described above, the higher the reaction temperature, particularly the aging temperature, is more effective for producing rod-shaped particles having a large pore diameter. On the other hand, the reaction solution is a strong acidic solution, and it is also important to carry out aging at a high temperature more easily. For this purpose, if the aging at a high temperature can be carried out in a neutral region without impairing the rod-like form, the production conditions are further relaxed. In order to solve these problems and produce the porous particles, a short rod-like organic inorganic mesostructure formed at a low temperature of 60 ° C. or lower is separated from an acidic solution by, for example, filtration, centrifugation, etc. After washing, this is possible by aging in an aqueous solution under hydrothermal conditions. Furthermore, it is also very effective to add an inorganic salt or an organic compound that is not isomorphously substituted with silica in the aging step. In this aging step, the product obtained by washing can be used in a wet state or after being dried.
In particular, it is clear that the addition of an inorganic salt or the like during hydrothermal treatment in an aqueous solution has a significant effect on improving the monodispersibility of the particles, and is effective in controlling pore characteristics such as mesopore diameter and pore volume. Is also effective.

Further, as is apparent from Table 1 shown for the examples described later, this production method is also characterized in that the aspect ratio and pore characteristics can be effectively controlled, particularly by controlling the acid concentration and the aging temperature. is there.
And as already pointed out, the production method of the present invention is an efficient method for producing porous silica particles having a uniform pore diameter in a wide range and exhibiting a rod shape of 0.5 μm or less. That is, rod-shaped porous silica particles having an aspect ratio of less than 0.1 to 1 can be synthesized with a simple reaction system without using a pore expanding agent such as an organic compound, and have a uniform pore diameter of 3.5 nm or more. It is a remarkable feature that rod-like porous silica particles can be provided.

  In the production method of the present invention, the aging time affects the macro form of the product and the pore characteristics such as the size of the mesopores and the regularity of the mesostructure. The longer the aging time, the higher the regularity of the mesostructure. As long as the condition of the rod-shaped particles of the present application is maintained, the aging time is not particularly limited.

  As described above, the reaction temperature in the production method of the present invention is in the range of 45 ° C. to less than 60 ° C., preferably in the range of 45 ° C. to 55 ° C. in the stirring step. The aging temperature is in the range of 50 ° C to 200 ° C, preferably in the range of 60 ° C to 150 ° C.

  In the production method of the present invention, in order to satisfy the condition that the rod-shaped porous silica particle precursor is generated by the stirring reaction in the initial stage, the mixing ratio of the reactants such as surfactant, acid, silica and the like, and further the stirring temperature It is possible to control the shape of the rod-like particles, the aspect such as the aspect ratio, and the pore characteristics by controlling the aging time and the aging temperature and time. In particular, by utilizing the fact that the hydrophilic part of the nonionic surfactant becomes hydrophobic in a high temperature state, when it is aged at 100 ° C. or higher, it has a pore size of 8 nm or more and a rod shape having a highly ordered mesostructure. Porous silica particles can be produced.

  In the present invention, the order of addition of the raw materials is extremely important. In order to form a rod-like form, an aqueous alkali silicate solution must be added to a nonionic surfactant solution dissolved in an acid. In the production method of the present invention, not only the heat treatment but also an extraction method using ethanol, ethanol / hydrochloric acid system can be applied as a method for removing the surfactant.

[material]
The silica raw material, nonionic surfactant, and acid used in the present invention will be further described.
As the silica raw material used in the present invention, alkali silicate can be used, and sodium silicate which is relatively inexpensive is preferable. As the sodium silicate, a sodium silicate aqueous solution having a composition in which m is a number of 1 to 5, particularly 1.5 to 4.5 in the Na ₂ O · mSiO ₂ formula is preferably used.

  As the nonionic surfactant, a polymer surfactant containing polyethylene oxide (PEO) can be used, and in particular, a triblock copolymer containing PEO is preferable, and further, polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-). The use of PPO-PEO) is optimal. The polymerization ratio, average molecular weight and hydrophobic group weight ratio of the triblock copolymer used in the present invention are important. The average molecular weight is about 4800 or more, and the hydrophobic group weight ratio is 60% or more by weight. It is desirable to be.

As the acid, any of hydrochloric acid, nitric acid, sulfuric acid, acetic acid and the like can be used, and hydrochloric acid which is most effective in producing rod-shaped particles is particularly preferable. Moreover, there is a possibility that various waste acids can be used as acids, which is considered useful for cost reduction.
In the method for producing rod-shaped porous silica particles of the present invention, the mixing molar ratio of the starting materials is SiO ₂ : nonionic surfactant: Na ₂ O: acid: water = 1: 0.01 to 0.1: It is preferable that it is 0.25-5: 5-20: 100-400.

The metal salt is not limited as long as a homogeneous transparent aqueous solution is formed and contains a metal element that does not substitute for Si in the silica skeleton. For example, NaCl, KCl, MgCl ₂ , AlCl ₃ , NiCl An anhydrous salt such as ₂ or a hydrate thereof can be used. The addition of the metal salt is intended to improve the monodispersibility, and the addition amount is 0.01 mol or more of the metal element with respect to 1 mol of SiO ₂ , and if the improvement of the monodispersity is recognized, the upper limit However, 1 mol or less is sufficient. The fact that the addition of a metal salt or the like in the ripening step is extremely effective for monodispersing rod-like particles is very characteristic in the present invention.

  Furthermore, the mixing method of the starting materials will be described in detail. In the rod-like particle synthesis of the present application, two kinds of aqueous solutions adjusted in advance to a temperature range of 45 ° C. to less than 60 ° C., (1) dissolved in an acid of a predetermined concentration (2) An aqueous alkali silicate solution diluted in water is added to the nonionic surfactant solution with stirring. Stirring of the mixed solution is stopped within a few seconds to 10 minutes in which no white turbidity due to the solid product is observed in the reaction solution, and the mixture is allowed to stand at a temperature higher than the stirring temperature or aged under stirring. As the aging method, (A) the stirred mixed solution is aged for 30 minutes or longer, preferably 1 hour or longer, more preferably 3 hours or longer to 24 hours, or (B) several seconds in which no cloudiness is observed as in (A) above. Stirring for 10 minutes to 10 minutes, and then aging for 10 minutes to 120 minutes, preferably 20 minutes to 90 minutes, and then separating and washing the precipitated product from the acidic reaction solution, or a wet solid product thereof, or The dried product is aged in the aqueous solution at the stirring temperature or higher as described above. Further, when (C) (A) and (B) both add a metal salt at the time of aging, in (A), after stirring is stopped, it is added directly to the stirred mixed solution, and in (B) a wet solid product, or its Metal salts are added when the dried product is aged.

  In any case, in order to obtain porous particles, the organic component is finally removed to produce rod-shaped porous silica particles. Dry at ℃. As a method of removing the surfactant after drying and making it porous, when removing by heat treatment, the heat treatment is finally carried out at 400 ° C. or higher for 2 hours or longer, preferably 500 ° C. or higher for 30 minutes or longer. The surfactant can also be removed by solvent extraction. In the case of ethanol alone, Soxhlet extraction or a dissolution method using a mixed aqueous solution of ethanol and acid can be applied.

[Usage]
Examples of the implantable material of the present invention include, but are not limited to, drug delivery carriers, gene introduction agents, immunostimulants, and additives to bioabsorbable polymers. In these applications, for example, the rod-shaped porous silica particles can be used for the purpose of reinforcing the strength of carriers or absorbent polymers for delivering drugs, genes, and immunostimulatory molecules into the body.

  Examples of the sustained-release silicon drug of the present invention include an immunostimulant, bone paste and its additive, bone cement and its additive, an additive to a coating layer of a metallic biomaterial, an oral administration agent and an injection. However, it is not limited to these. In these applications, the rod-like porous silica particles can be used for the purpose of promoting cell growth or inducing a biological reaction such as an immune reaction by gradually releasing silicon.

  The rod-shaped porous silica particles of the present invention can be dispersed or suspended in a liquid medium to obtain a suspension or dispersion (particle solvent mixed system). By dispersing in the liquid medium, the rod-shaped porous silica particles contained in the liquid medium can be effectively administered to humans and animals. As a result of maintaining the rod-like porous silica particles in a dispersed state in the liquid medium in this manner, the suspension or dispersion liquid (particle solvent mixed system) of the present invention is an oral administration agent, parenteral administration agent, attachment agent, It can be used as an ointment, suppository, etc., and can be directly administered to a living body, and as a result, high biocompatibility can be obtained.

The amount of rod-shaped porous silica particles added to disperse and suspend rod-shaped porous silica particles in a liquid medium is calculated by calculating the total amount of rod-shaped porous silica particles required. The result will be the dose.
Based on the calculated dose, the amount of the liquid medium may be appropriately determined so that the fine particle sedimentation rate determined in consideration of the viscosity of the liquid is within the intended range.

  The mixing ratio of the particles and the liquid solvent in the suspension or dispersion is the viscosity of the suspension or dispersion (particle solvent mixed system) containing rod-shaped porous silica particles that enables therapeutic action such as administration. It is defined from the viewpoint of That is, the entire viscosity of the suspension or the particle solvent mixed system can be kept at 3000 Pa s or less, preferably 300 Pa s or less for 2 seconds or more, preferably 10 seconds or more at room temperature. If it is less than this, there is no particular problem. Since the viscosity of the suspension can be used without any problem even when it is close to water, the lower limit of the viscosity is 1.00 mPa s corresponding to the viscosity value of water at 20 ° C.

  The upper limit of the viscosity was set to 3000 Pas because the following matters were taken into consideration. In other words, the viscosity of 3000 Pas corresponds to the melt viscosity at 260 ° C. of polyamide MXD6-G having a molecular weight of 40,000. If the viscosity is higher than this, the liquid will actually lose its fluidity, and even if it is pressurized, the syringe or catheter must be It is a state where it cannot pass through, or a state where it cannot be deformed by hand like an ointment. As is clear from this, when the viscosity of the suspension or particle solvent mixture system exceeds 3000 Pas, it can be administered into the body using a syringe or catheter, or used as an attachment or ointment. It means a state that cannot be done.

In the suspension or dispersion liquid (particle solvent mixed system) of the present invention in which the rod-like porous silica particles thus obtained are in a dispersion suspension state, the rod-like porous silica particles are at least 2 seconds. As described above, it is necessary that the suspended state be maintained for a time of 10 seconds or more.
For this purpose, it is preferable to contain 2 to 300 μg / mL of rod-like silica porous particles in the suspension or dispersion.
When administered to humans or animals, it is necessary to administer in a dispersed suspension state. When administered, the suspension state is maintained for a specific time, so that the rod-shaped porous silica particles are formed. As described above, it can be administered to humans and animals.
For example, the dispersion suspension composition of rod-shaped porous silica particles is used by being injected into or filling a container such as a container for internal use (cup) or a syringe. These containers or syringes have a depth or height of about 8 cm at the maximum. The rod-like porous silica particles are adjusted so that the particle sedimentation rate is 4 cm / s or less, preferably 0.8 cm / s or less. As a result, the dispersion suspension state is maintained in the container for a time of 2 seconds or longer, preferably 10 seconds or longer. When this amount of time is secured, the time necessary for administration to humans and animals is maintained.

  Solvents for making a suspension or dispersion (particle solvent mixed system) include water, physiological saline, saline with a salt concentration of 2.5% by weight or less, Ringer's solution, purified water, water for injection, distilled water, physiological salts Water-soluble solvent selected from solution, propylene glycol, ethanol, propylene glycol containing these waters, or ethanol containing these waters, or triglyceroid, safflower oil, soybean oil, sesame oil, rapeseed oil, peanut A water-insoluble solvent selected from oils or polyethylene glycol (macrogol) can be mentioned.

  The fact that rod-shaped porous silica particles can be used as an in vivo material without showing cytotoxicity is that, for example, mouse-derived fibroblast-like cells NIH3T3 are contained in cell culture medium containing and not containing rod-shaped porous silica particles. It can be confirmed that the number of cells in the culture medium containing rod-shaped porous silica particles is not statistically significantly lower than the number of cells in the cell culture liquid not containing rod-shaped porous silica particles.

  The fact that rod-shaped porous silica particles can be used as a sustained-release silicon drug without showing cytotoxicity is that, for example, mouse-derived fibroblast-like cells NIH3T3 are 3 in cell culture medium containing and not containing rod-shaped porous silica particles. The supernatant after culturing for a day and centrifuging the medium containing rod-shaped porous silica particles is chemically analyzed by inductively coupled plasma optical emission spectrometry (ICP) to increase the silicon content, and rod-shaped porous silica The number of cells in the particle-containing culture medium can be confirmed by statistically significantly exceeding the number of cells in the rod-shaped porous silica particle-free cell culture medium.

EXAMPLES Next, although an Example demonstrates this invention further more concretely, this invention is not limited by this Example.
In addition, each test method performed in the Example was performed by the following method.
(Measurement method)
(1) Morphology and particle size: Using a scanning electron microscope JSM5300 manufactured by JEOL Ltd., observation was performed at an acceleration voltage of 10 kV and a WD of 10 mm. Furthermore, form observation was performed using Hitachi field emission scanning electron microscope S-4700F, and the aspect ratio was determined from the image data.
(2) Specific surface area, pore volume, pore diameter distribution: BEL specific surface area was determined from the nitrogen adsorption isotherm measured at liquid nitrogen temperature using BELSORP MINI manufactured by Bell Japan, and the pore volume was finer than the t-plot. The pore volume (sum of mesopore volume and micropore volume) and the micropore volume were calculated separately, and the pore size distribution was analyzed by the BJH method.
(3) X-ray diffraction: Rigaku Rotorflex RU-300 was used and measured with a CuKα radiation source, an acceleration voltage of 40 kV, and 80 mA.
(4) Transmission electron microscope observation (TEM): A high-resolution electron microscope HF-2000 manufactured by HITACHI was used and observed at an acceleration voltage of 200 kV.
(5) Particle size distribution: LS 13 320 manufactured by Beckman Coulter, Inc. was used, and a sample suspended in water was dispersed and measured with an ultrasonic cleaner for 1 hour to obtain a volume-based particle size distribution curve.

Example 1
The triblock copolymer Pluronic P123 (PEO ₂₀ PPO ₇₀ PEO ₂₀ ) solution dissolved in hydrochloric acid is stirred at a predetermined temperature of 35 ° C. or higher to completely dissolve the solution, and then the acid solution is diluted with water in advance. Commercially available JIS No. 3 sodium silicate (SiO ₂ : 23.6%, Na ₂ O: 7.59%) in a separate container kept at a predetermined temperature of at least ° C. is added with stirring. In this example, it is important that crystallization of white precipitates is not observed at all before aging, and the stirring time is 30 seconds for all. After stirring is stopped, the mixture is transferred to a Teflon (registered trademark) container and sealed. Aging was carried out for 6 hours in a dryer sealed in a pressure vessel made of stainless steel and previously controlled at a predetermined temperature.
The molar ratio of the mixed solution of this example is SiO ₂ : Pluronic P123: Na ₂ O: HCl: H ₂ O = 1: 0.017: 0.312: 5-12: 190-202. H ₂ O contains water derived from all raw materials. After the reaction, the solid product is filtered off, washed and sufficiently dried at 65 ° C. Finally, the organic component is removed by baking in an electric furnace at 600 ° C. for 1 hour to obtain rod-shaped porous silica particles.
Table 1 shows the synthesis conditions of this example, the parameters relating to the shape such as the aspect ratio of the obtained rod-shaped porous silica particles, and the pores such as the BET specific surface area, the total pore volume, the micropore volume, and the mesopore diameter. Show the characteristics. As the aging temperature increases, the pore diameter increases, and rod-shaped porous silica particles having a pore diameter of 8 nm or more are obtained at 100 ° C. or higher. When the stirring temperature is 50 ° C. and ripening is performed at the same temperature, as shown in Comparative Example 1 (FIG. 3), rod-shaped particles are difficult to produce, but the ripening is performed at a higher temperature. The rod-shaped porous silica particles of the present application can be produced as described in. FIG. 5 shows the rod-shaped porous silica particles of Example 1-1, which has a micron-sized rod-like form, the form of individual particles is clear, and the rod-like particles having an aspect ratio of 1 or less loosely aggregate. In other words, it exists as an aggregate of about 10 μm.

(Example 2)
The triblock copolymer Pluronic P123 (PEO ₂₀ PPO ₇₀ PEO ₂₀ ) solution dissolved in hydrochloric acid is stirred at a predetermined temperature of 35 ° C. or more to completely dissolve the solution, and then the acid solution is diluted with water in advance. Commercially available JIS No. 3 sodium silicate (SiO ₂ : 23.6%, Na ₂ O: 7.59%) in a separate container kept at a predetermined temperature of at least ° C. is added with stirring. In this example, it is important that no crystallization of a white precipitate is observed before aging, and the stirring time is 30 seconds for all. After stopping stirring, aging is performed for 1 hour at the same temperature as stirring. The obtained rod-shaped porous silica particle precursor was filtered and washed, then transferred to a sealed reaction vessel in the same manner as in Example 1 in a wet state, added with water, and kept in a thermostatic bath at 100 ° C. or 150 ° C. for 6 hours. Hydrothermal treatment was performed. In the hydrothermal treatment, the amount of water added is about 24 g in terms of 1 g of the dried precursor. The mixing molar ratio of the reaction solution is SiO ₂ : Pluronic P123: Na ₂ O: HCl: H ₂ O = 1: 0.017: 0.312: 8-11: 190-200. H ₂ O contains water derived from all raw materials. After hydrothermal treatment, the solid product is filtered off, washed and dried at 65 ° C. Finally, the organic component is removed by baking in an electric furnace at 600 ° C. for 1 hour to obtain rod-shaped porous silica particles.
Table 1 shows the synthesis conditions of this example, the parameters relating to the shape such as the aspect ratio of the obtained rod-shaped porous silica particles, and the pores such as the BET specific surface area, the total pore volume, the micropore volume, and the mesopore diameter. Show the characteristics.
FIG. 6 is an FE-SEM image of Example 2-1. The morphology of individual particles is clear, and rod-shaped particles having an aspect ratio of 1 or less are loosely aggregated, but the particle size of FIG. 8 (FIG. 9). The degree of aggregation is weakened from the distribution, and a particle size distribution peak is observed at a particle size of about 5 μm. From the particle size distribution of Comparative Example 3 in FIG. 8, it is clear that the aging step under hydrothermal conditions of the present application is effective for improving the monodispersibility.

(Example 3)
The triblock copolymer Pluronic P123 (PEO ₂₀ PPO ₇₀ PEO ₂₀ ) solution dissolved in hydrochloric acid is stirred at a predetermined temperature of 35 ° C. or more to completely dissolve the solution, and then the acid solution is diluted with water in advance. Commercially available JIS No. 3 sodium silicate (SiO ₂ : 23.6%, Na ₂ O: 7.59%) in a separate container kept at a predetermined temperature of at least ° C. is added with stirring. In this example, it is important that no crystallization of a white precipitate is observed before aging, and the stirring time is 30 seconds for all. After stopping stirring, aging is performed for 1 hour at the same temperature as stirring. After the obtained rod-shaped porous silica particle precursor was filtered and washed, it was transferred to a sealed reaction vessel in the same manner as in Example 1 in a wet state, and an aqueous solution in which a metal salt was dissolved was added. Hydrothermal treatment was performed at 150 ° C. for 6 hours. In the hydrothermal treatment, the amount of water added is about 24 g in terms of 1 g of the dried precursor. In this embodiment, NaCl, MgCl ₂ .6H ₂ O, AlCl ₃ .6H ₂ O, and NiCl ₂ .6H ₂ O are used as metal salts, and the addition amount is 0.1 mol of NaCl with respect to 1 mol of SiO ₂ . 17 mol, others are 0.085 mol, and the mixing molar ratio of the reaction solution is SiO ₂ : Pluronic P123: Na ₂ O: HCl: H ₂ O = 1: 0.017: 0.312: 8-11: 190- 200. H ₂ O contains water derived from all raw materials. After hydrothermal treatment, the solid product is filtered off, washed and dried at 65 ° C. Finally, the organic component is removed by baking in an electric furnace at 600 ° C. for 1 hour to obtain rod-shaped porous silica particles.
Table 1 shows the synthesis conditions of this example, the parameters relating to the shape such as the aspect ratio of the obtained rod-shaped porous silica particles, and the pores such as the BET specific surface area, the total pore volume, the micropore volume, and the mesopore diameter. Show the characteristics.
FIG. 7 is an FE-SEM image of Example 3-4. The morphology of individual particles is clear, and rod-like particles having an aspect ratio of 1 or less are loosely aggregated. From the particle size distribution of FIG. The degree is weakened, and a particle size distribution peak is observed at a particle size of about 5 μm. From the particle size distribution of Comparative Example 3 in FIG. 8 and Example 2-1, it is clear that the aging step under hydrothermal conditions with the addition of the metal salt of the present application is extremely effective in improving monodispersity.

(Example 5)
1 mL of a cell culture solution containing 1 × 10 ⁴ fibroblast-like cells NIH3T3 was poured into each well of a 24-well plate and precultured for 6 hours. The cell culture medium was prepared by adding L-glutamine (0.3 mg · mL ⁻¹ ) and 10% bovine serum to DMEM medium. After the preculture, the same cell culture medium was replaced with a cell culture medium containing rod-shaped porous silica particles 0, 5, 20, 50, 100 and 300 μg / ml. The rod-shaped porous silica particles used are Examples 3-4 and 3-5. Thereafter, NIH3T3 cells were cultured in a 5% carbon dioxide atmosphere for 72 hours, and the number of cells was measured by the WST-8 method using a CCK-8 kit (Dojin Kagaku, Japan). WST-8 is reduced by intracellular dehydrogenase to produce water-soluble formazan. If the absorbance of this formazan is measured at 450 nm, the absorbance becomes an indicator of the number of cells.
In addition, the cell culture solution (1 ml) after 72 hours was collected and centrifuged to settle the rod-shaped porous silica particles, and then 0.5 mL of the supernatant was recovered and diluted to 5 mL with ultrapure water to induce induction binding. The silicon content was measured by plasma emission spectrometry (ICP). For each rod-like porous silica particle, the number of cells was tested by one-way analysis of variance. If a significant difference was detected, the significant difference between groups was tested by Tukey's post hoc multiple comparison test. Experiments were performed at N = 8 and all statistical analyzes were performed at a significance level of 5%.

15 and 16 show the cell number evaluation results after 72 hours of culture of NIH3T3 cells together with the rod-shaped porous silica particles of Examples 3-4 and 3-5. All the rod-like porous silica particles had a statistically significantly smaller number of cells compared to 0 μg / ml when the content in the cell culture medium was 300 μg / ml, but 5,20,50,100 μg / ml There was no statistically significant difference in the concentration of ml compared to 0 μg / ml, or the number of cells was statistically significant. Moreover, silicon eluted in the cell culture medium could be detected by ICP, and the amount of eluted silicon increased with increasing rod-shaped porous silica particle concentration (FIG. 17).

  The concentration of rod-shaped porous silica particles at 5, 20, 50, and 100 μg / ml does not show a statistically lower number of cells compared to 0 μg / ml. This means that there is no cytotoxicity of silica particles, and it has been shown that rod-like porous silica particles can be used as in vivo implants. Further, in the case of Example 3-4, the content was 5, 20, 50, 100 μg / ml, and in the case of Example 3-5, the content was 100 μg / ml, and the number of cells was compared with the content of 0 μg / ml. This means that the silicon released from the rod-shaped porous silica particles within this range promoted cell growth, and the rod-shaped porous silica particles showed cytotoxicity. It was shown that it can be used as a silicon sustained release agent.

(Comparative Example 1)
The triblock copolymer Pluronic P123 (PEO ₂₀ PPO ₇₀ PEO ₂₀ ) solution dissolved in 2N hydrochloric acid is completely dissolved by stirring at 50 ° C., and then diluted with water in advance and kept at 50 ° C. In another container, commercially available JIS No. 3 sodium silicate (SiO ₂ : 23.6%, Na ₂ O: 7.59%) was added and mixed, and stirring was stopped after 30 seconds. This mixed solution was left as it was in a constant temperature water bath and aged at 50 ° C. for 300 minutes. The molar ratio of the reaction solution is SiO ₂ : Pluronic P123: Na ₂ O: HCl: H ₂ O = 1: 0.017: 0.312: 5.88: 202. H ₂ O contains water derived from all raw materials. After the reaction, the solid product is filtered off, washed and sufficiently dried at 65 ° C. Finally, the organic component is removed by baking in an electric furnace at 600 ° C. for 1 hour to obtain rod-shaped porous silica particles.
From the SEM image (FIG. 3), it can be seen that in the product obtained in this comparative example, the small particles strongly aggregate and the desired monodispersed rod-like particles cannot be obtained. Furthermore, as shown in Table 2, no clear steps due to the mesostructure were observed in the adsorption isotherm of this comparative example, and the pore characteristic parameters were all very small, especially when the synthesis temperature was 50 ° C. Nevertheless, it is clear that the mesopore diameter is small and the structural regularity is very low.

(Comparative Example 2)
A triblock copolymer Pluronic P123 (PEO ₂₀ PPO ₇₀ PEO ₂₀ ) solution dissolved in 2N hydrochloric acid was completely dissolved by stirring at 45 ° C., then diluted with water in advance and kept at 45 ° C. In another container, tetraethylorthosilicate (TEOS) was added and mixed, and stirring was stopped after 30 seconds. After stopping the stirring, the mixture was aged at 100 ° C. for 6 hours using a sealed container. The molar ratio of this reaction solution is TEOS: Pluronic P123: HCl: H ₂ O = 1: 0.017: 5.85: 201.
Also, the triblock copolymer Pluronic P123 solution dissolved in 2N hydrochloric acid is completely dissolved by stirring at 45 ° C., and then NaCl is added to perform synthesis similar to the above to examine the effect of adding NaCl. did. The molar ratio of this reaction solution is TEOS: Pluronic P123: HCl: H ₂ O: NaCl = 1: 0.017: 5.85: 201: 1.49.
In either case, the solid product after the reaction is filtered off, washed, sufficiently dried at 65 ° C., and finally baked in an electric furnace at 600 ° C. for 1 hour to remove organic components and powder Get particles.
4A and 4B are SEM images of Comparative Example 2-1 and Comparative Example 2-2 in Table 2, respectively. In the case of TEOS, stirring and ripening reaction are performed at a constant temperature. At 45 ° C., the particle morphology is inhomogeneous and the desired particles are not formed. Further, when the mixture is stirred at 45 ° C. and ripened at 100 ° C., when no NaCl is added, long rod-shaped particles having an aspect ratio of 1 or more are formed (FIG. 4 a). In addition to the long rod-like particles, aggregates of small particles are observed (FIG. 4b). The addition of salt greatly affects the morphology of the rod-shaped particles, suggesting that sodium silicate is a silica raw material suitable for the synthesis of rod-shaped particles having a small aspect ratio.
There is no clear step due to the mesostructure in the adsorption isotherm of this comparative example. Compared with Examples 1, 2 and 3 in Table 1, all the pore characteristic parameters shown in Table 2 are small. I understand.

(Comparative Example 3)
A triblock copolymer Pluronic P123 (PEO ₂₀ PPO ₇₀ PEO ₂₀ ) solution dissolved in 2N hydrochloric acid was completely dissolved by stirring at 38 ° C. or 45 ° C. Then, water was added to the acidic solution in advance for dilution. Commercially available JIS No. 3 sodium silicate (SiO ₂ : 23.6%, Na ₂ O: 7.59%) in a separate container kept at a temperature of 5 ° C. was added and mixed, and stirring was stopped after 30 seconds. The mixed solution was left as it was in a constant temperature water bath and aged for 6 hours. The molar ratio of the reaction solution is SiO ₂ : Pluronic P123: Na ₂ O: HCl: H ₂ O = 1: 0.017: 0.312: 5.88: 202. H ₂ O contains water derived from all raw materials. After the reaction, the solid product is filtered off, washed and sufficiently dried at 65 ° C. Finally, the organic component is removed by baking in an electric furnace at 600 ° C. for 1 hour to obtain rod-shaped porous silica particles.
This comparative example corresponds to the rod-shaped particles of Patent Document 2, and the target monodispersed rod-shaped particles are obtained by aggregation more strongly than the rod-shaped particles of the present application from the particle size distribution shown in FIG. I can't understand.

Claims (14)

Through transmission and scanning microscope observation, the particle length in the direction through which the one-dimensional channel-shaped pores with a mesopore diameter of 3 nm or more arranged in a honeycomb shape penetrate is 0.5 μm or less, and the particles are perpendicular to the particle stretching direction. When the ratio to the length of the cross section is the aspect ratio (= the length of the particle in the direction through which the pore penetrates / the length of the cross section of the particle perpendicular to the particle extension direction) , the aspect ratio is less than 0.1 to 1 The Si element in the silica skeleton forms a loose aggregate with a maximum particle size distribution peak (volume basis) of 10 μm or less in a water dispersion system. rod porous silica particles to feature that it is not substituted by other metals.   2. The rod-shaped silica porous particle according to claim 1, which has a plurality of X-ray diffraction peaks showing a regular arrangement structure of pores at a diffraction angle of 0.5 to 5 degrees (CuKα).   A suspension or dispersion containing 2 to 300 µg / mL of the rod-like silica porous particles according to claim 1 or 2.   An alkaline silicate aqueous solution is mixed with a mixed solution of an acidic aqueous solution and a nonionic surfactant while stirring under a temperature condition of 45 ° C. to less than 60 ° C., and the reaction solution is stirred within a reaction time in which no cloudiness is observed. The nonionic surfactant is removed from the solid product obtained by aging at a temperature in the range of 50 ° C to 200 ° C after stopping, after separating, washing and drying. Item 3. A method for producing rod-like silica porous particles according to Item 2.   An alkaline silicate aqueous solution is mixed with a mixed solution of an acidic aqueous solution and a nonionic surfactant while stirring under a temperature condition of 45 ° C. to less than 60 ° C., and the reaction solution is stirred within a reaction time in which no cloudiness is observed. After stopping and aging for 10 to 120 minutes, the solid product obtained by separation and washing is either wet or dried and then aged in an aqueous solution at a temperature in the range of 50 ° C to 200 ° C. 3. The method for producing rod-shaped silica porous particles according to claim 1, wherein the solid product is separated, washed, and dried, and then the nonionic surfactant is removed.   An alkaline silicate aqueous solution is mixed with a mixed solution of an acidic aqueous solution and a nonionic surfactant while stirring under a temperature condition of 45 ° C. to less than 60 ° C., and the reaction solution is stirred within a reaction time in which no cloudiness is observed. The solid product obtained by stopping, aging for 10 to 120 minutes, and separating and washing is left in a wet state or dried and then in an aqueous solution in which the metal salt is dissolved. The method for producing rod-shaped silica porous particles according to claim 1 or 2, wherein the solid product is separated, washed and dried after aging at a temperature, and then the nonionic surfactant is removed. . The method according to any one of claims 4 to 6 non-ionic surfactant is characterized by using an amount of SiO ₂ 1 mole per 0.01 to 0.10 mole of the alkaline silicate. The method according to any one of claims 4 to 7, wherein the acid is used in an amount of 5 to 20 moles per mole of SiO ₂ in the alkali silicate. The method according to any one of claims 4 to 8, wherein water is used in an amount of 100 to 400 mol per mol of SiO ₂ in the alkali silicate. The production method according to any one of claims 6 to 9, wherein the metal salt is used in an amount of 0.01 to 1 mol per mol of SiO ₂ in the alkali silicate.   An in-vivo embedding material containing the rod-shaped porous silica particles according to claim 1 or 2.   A silicon sustained-release drug comprising the rod-shaped porous silica particles according to claim 1 or 2.   An in vivo embedding material containing the suspension or dispersion according to claim 3.   A silicon sustained-release drug comprising the suspension or dispersion according to claim 3.